Flowometry in optical coherence tomography for analyte level estimation

ABSTRACT

Optical coherence tomography (herein “OCT”) based analyte monitoring systems are disclosed. In one aspect, techniques are disclosed that can identify fluid flow in vivo (e.g., blood flow), which can act as a metric for gauging the extent of blood perfusion in tissue. For instance, if OCT is to be used to estimate the level of an analyte (e.g., glucose) in tissue, a measure of the extent of blood flow can potentially indicate the presence of an analyte correlating region, which would be suitable for analyte level estimation with OCT. Another aspect is related to systems and methods for scanning multiple regions. An optical beam is moved across the surface of the tissue in two distinct manners. The first can be a coarse scan, moving the beam to provide distinct scanning positions on the skin. The second can be a fine scan where the beam is applied for more detailed analysis.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/063977, filed Oct. 25, 2013, titled “Flowometry in OpticalCoherence Tomography for Analyte Level Estimation,” which is acontinuation of U.S. patent application Ser. No. 12/397593, filed Mar.4, 2009, titled “Flowometry in Optical Coherence Tomography for AnalyteLevel Estimation,” which claims the benefit of U.S. ProvisionalApplication No. 61/068058, filed Mar. 4, 2008, titled “Flowometry inOptical Coherence Tomography for Analyte Level Estimation,” and U.S.Provisional Application No. 61/033584, filed Mar. 4, 2008, titled“Multispot Monitoring for Use in Optical Coherence Tomography.” Thepresent application is also related to U.S. patent application Ser. No.12/397,577, filed Mar. 4, 2009, titled “Multispot Monitoring for Use inOptical Coherence Tomography.” The entirety of each of theabove-mentioned applications is hereby incorporated by reference hereinfor all purposes.

BACKGROUND

The present application relates to methods and devices for performingmeasurements with optical coherence tomographic techniques, and in someinstances particularly for detecting analytes using optical coherencetomography.

Optical coherence tomography (herein “OCT”) is an optical imagingtechnique that has shown great promise for use in many applications suchas glucose monitoring. In this sensor modality, the high depthresolution of this technique is able to measure, with a high degree ofaccuracy, the scattering properties of a subject's tissue (e.g., theskin). These scattering properties can be sensitive to the changes inanalyte levels in a subject's tissue. e.g., blood glucose levels in asubject. Thus, changes in the OCT signal can be correlated with changesin the analyte levels and thus serve as a prospective predictor ofchanges in that subject's analyte levels.

While OCT-based devices and techniques have shown promise in detectinganalytes such as glucose, improvements are still needed. For instance,improvements in the speed and ease with which such techniques can beapplied could help commercial acceptability of such devices.Accordingly, a need persists to provide improved OCT devices andtechniques, which can provide accelerated estimates of analyte levels ina subject's tissue in an easy to use and reliable manner.

SUMMARY

Optical coherence tomography (herein “OCT”) based analyte monitoringsystems are disclosed. In one aspect, techniques are disclosed that canidentify fluid flow in vivo (e.g., blood flow), which can act as ametric for gauging the extent of blood perfusion in tissue. Forinstance, if OCT is to be used to estimate the level of an analyte(e.g., glucose) in tissue, a measure of the extent of blood flow canpotentially indicate the presence of an analyte correlating region,which would be suitable for analyte level estimation with OCT. Anotheraspect is related to systems and methods for scanning multiple regions.An optical beam is moved across the surface of the tissue in twodistinct manners. The first can be a coarse scan, moving the beam toprovide distinct scanning positions on the skin. The second can be afine scan where the beam is applied for more detailed analysis.

Some aspects of the present invention are directed to techniques whichcan detect fluid flow in vivo (e.g., blood flow) using optical coherencetomography (herein “OCT”). Such techniques can utilize the speckle froman OCT scan and/or the fringe-frequency modulation to identify flow.Detection of flow by OCT can be used in a variety of applications suchas heart monitoring or imaging of fluid flow in a non-invasive manner.In some embodiments, OCT is applied to detect blood flow, which can actas a metric for gauging the extent of blood perfusion in tissue. Forinstance, if OCT is to be used to estimate the level of an analyte(e.g., glucose) in tissue, a measure of the extent of blood flow canpotentially indicate the presence of an analyte correlating region(herein “ACR”) which would be suitable for analyte level estimation withOCT. While not necessarily being bound by any particular theory, if aparticular analyte is typically associated with blood (e.g., related tothe presence of arterioles and venules), the identification of bloodperfused tissue can act as a marker of where detailed OCT measurementsand/or analysis of measurements should be performed to obtain estimatesof analyte levels. Accordingly, some embodiments are directed to methodsand device for analyte level estimation using OCT, where OCT scanningcan identify tissue regions having blood flow that are suitable foranalyte estimation.

For example, exemplary embodiments are drawn toward systems and methodsof determining blood analyte levels in a tissue sample using opticalcoherence tomography (OCT). In an exemplary method, a plurality ofregions in the tissue sample are scanned using OCT to providecorresponding intensity data measurements. Each tissue region can beraster scanned to provide the intensity data. The tissue regions canoptionally be scanned over multiple depths. The intensity measurementscan include signals from backscattered light and/or can exhibit speckle.The intensity data measurements, and/or speckle, can be analyzed todetermine whether blood flow is present in the corresponding region.Blood analyte levels can be obtained from one or more of the regionshaving blood flow present as analyzed from the OCT measurements.

Scanning of a tissue sample can be performed in a variety of manners. Insome instances, multiple regions are scanned over multiple moments intime to provide the intensity measurements. Comparison of intensitydata, which can exhibit speckle, taken over the multiple time momentscan be used to determine whether blood flow is present. In someinstances, intensity data measurements are compared over multiple tissueregions to determine whether blood flow is present.

Other aspects of the invention are directed to systems for determiningat least one blood characteristic in a tissue sample. The system cancomprise an OCT apparatus configured to obtain intensity datameasurements from a plurality of regions in the tissue sample. Suchsystems can be consistent with any of the OCT systems disclosed in thepresent application and/or those within the knowledge of one skilled inthe art. The system can further comprise a processor configured toanalyze the intensity data measurements from the OCT apparatus todetermine whether blood blow is present in at least one region. In someinstances, the system can be configured to provide different intensitydata measurements over a plurality of regions and a plurality of depths.The system can also be configured to provide raster scans of a pluralityof regions. Systems that provide scanning over different regions canutilize a beam scanner, which can be appropriately configured to achievethe desired scanning modality. In some embodiments, the OCT apparatuscan be configured to provide different intensity data measurements overa plurality of moments in time.

In related embodiments, the processor can be configured to convert theintensity data measurements into analyte levels (e.g., blood glucoselevels). The processor can be configured to analyze speckle in theintensity data measurements and optionally compare those measurements todetermine whether blood flow is present. In other embodiments, theprocessor can analyze fringe-modulated data, such as high frequencycomponents and/or amplitude modulation. The processor can also comprisea signal filter for converting at least a portion of the intensity datameasurement into a reduced intensity signal, which can indicate thepresence of blood flow through the correlation with fringe frequencymodulation. The signal filter can comprise a narrow and/or wide bandfilter to convert at least a portion of the intensity data measurementsinto an attenuated output, with the processor optionally configured tocompare the reduced intensity signal and the attenuated output todetermine the presence of blood flow.

In some exemplary embodiments, a method is utilized to determine thepresence of fluid flow in tissue using OCT. These embodiments canoptionally be combined with other steps to determine blood analytelevels, as described herein. A tissue sample can be scanned over each ofone or more tissue regions, for example at various depths, to obtaincorresponding fringe-modulated data, which can be analyzed to determinethe presence of blood flow. The fringe-modulated data to be analyzed caninclude determining a peak fringe frequency shift, or analyzing theamplitude modulation in the data, to determine whether blood flow ispresent. In the latter case, selected high frequency components of theintensity data, which can be related to speckle, can be analyzed todetermine whether blood flow is present. In some instances, theintensity data measurements having fringe-modulated data can be passedthrough a filter, wherein the filter is configured to produce a filteredsignal indicating fringe frequency modulation indicative of blood flow'spresence. For example, the intensity data measurements can be passedthrough a narrow band filter, which can be configured to produce areduced intensity signal output from an intensity data measurementexhibiting blood flow. Optionally, the intensity data measurements canalso be passed through a wide band filter, which can be configured toproduce an attenuated output exhibiting at least one fringe-modulatedfeature from an intensity data measurement exhibiting blood flow.Subsequently, the reduced intensity output and the attenuated output canbe compared to determine whether blood flow is present. Digital signalprocessing, analog signal processing, or a combination of the twotechniques can be utilized to analyze the intensity data measurements inany fashion.

Other aspects of the present invention are directed to methods, devices,and/or systems that can scan multiple tissue sites. Tissue sites caneach be scanned using an optical coupler, which can be attached to asingle location on a subject's skin; each tissue site can also, oralternatively, be associated with a separate potential analytecorrelating region (herein “ACR”) or be separated by a distance at leastas large as some distance associated with an ACR. An assessment of thequality of each tissue site to provide acceptable analyte levels (i.e.,that the site is a ACR) can be made, followed by analyzing OCT data atone or more of the identified ACRS to provide an estimate of an analytelevel in the scanned tissue. Other aspects of devices and methods thatembody some or all of these features are included in the presentapplication.

For instance, some embodiments are drawn toward OCT-based analytemonitoring systems in which the optical interrogation beam is movedacross the surface of the tissue in two distinct ways. The first is acoarse tune of the beam position, moving the beam over a large distancein order to provide positions on the skin that are spatially distinctfrom each other. The second is a fine scan where the beam is appliedover one or more smaller areas that are selected by a controller formore detailed analysis.

Coarse position tuning over a large area of tissue can be useful whenthe tissue is inhomogeneous so that regions of little or no analyticvalue can be ignored or discounted, and/or regions of high analyticcontent can be identified for future analysis. For example, hairs withtheir associated structures (i.e., sebaceous glands, erector muscles,etc.) can be avoided. These structures are large and, due to the depthat which their blood vessels lie, have little to no associated perfusionin the dermis. Thus, coarse scanning over a large spatial area allowsthe sensor to avoid such structures. Another example is an arterioleand/or venule plexus, a highly perfused region of tissue, and adesirable scanning location for the sensor. These structures are moresparsely distributed and thus coarse scanning over a large area isdesirable to ensure that such a plexus can be located. In both cases,the location of these structures cannot easily be discerned by the nakedeye and thus the sensor can also accommodate for sub-optimal sensorplacement by the user.

The fine or raster portion of the scan can provide a smaller region oftissue from which data is obtained to correlate to glucose changes. Thefine scan takes advantage of the high spatial resolution of the systemand allows regions of the tissue with a high density of analytecorrelating regions (ACRS) to be monitored, improving the systemresponse to glucose.

Some exemplary embodiments are drawn toward optical coherence tomography(OCT) systems for determining an analyte level in tissue. The systems,which can optionally be a non-imaging system unlike many other OCTsystems, can include a light source for generating skin-penetratingradiation suitable for OCT measurements and a detector for receivingreflected light from the skin-penetrating radiation. An interferometercan be coupled to the system to form a combined signal from thereflected light from the skin and a reference beam, the combined signalbeing received by the detector. A phase shifter can be included andconfigured to shift the phase of the reference beam, which can providetissue depth scanning.

A beam scanner can be included for directing a beam of radiation fromthe source to a plurality of sites to provide a measure of analytelevels (e.g., glucose levels) in the tissue at one or more of the sites.Each site can be associated with a different analyte correlating region.For instance, each site can include a non-overlapping area (e.g., eachsite being a unique spatial area) relative to all other sites. The sitescan form a selected pattern and/or substantially cover a designatedlarger tissue area. The beam scanner can scan within a tissue site in avariety of manners. For example, the scanner can scan the entire area ofat least one of the plurality of sites and/or scan in a manner toprovide an aggregated OCT measurement that has reduced speckle content.Scanning within a tissue area can be conducted to provide OCT datasufficient to provide an analyte level estimation and/or sufficient toprovide a measure of validity of a tissue site as an ACR.

In some embodiments, a beam scanner, which can be part of an OCTapparatus for detecting analyte levels in scanned tissue, can beconfigured to adjust movement of a beam on at least two-different lengthscales. One of the length scales can be a site-scale where the beammoves over a distance large enough such that the beam scanner probes aplurality of tissue sites. Another length scale can be ameasurement-scale wherein the beam moves over a distance smaller thanthe site-scale. OCT measurements can be taken over the measurement-scalesuch that the data obtained can provide analyte measurement correlation.

Beam scanners can include one or more optical elements (e.g., mirror orrotatable prism) configured to move a beam of radiation. For instance arotatable prism can be used to move the beam to a variety of tissuesites, while a moveable mirror can provide scanning within a tissuesite. Other types of devices, such as a flexure, can also be used tocontrol optical element movement.

Also, a controller can be included for selecting sites from theplurality of sites for monitoring. The controller can be integrated intoa single unit with a beam scanner, or be a separate device coupled tothe beam scanner. The controller can be configured to associate OCTmeasurements with each of the plurality of sites, and can subsequentlyprovide an aggregated measure of the analyte level using OCTmeasurements from a plurality of sites. OCT measurements can correspondwith a measure of an analyte level in the scanned tissue. In someinstances, the controller can be configured to select one or more sitesbased on whether a site is validated for analyte level measurement(e.g., whether the site is validated based upon a tissue hydrationlevel). OCT measurements from one or more validated site scan be used tocalibrate an OCT system.

Some embodiments are directed toward a structure for providing acoupling between an optic and a subject during OCT measurements. One ormore optical elements can be optically couplable to an OCT system toguide reflected light. A patch for aligning the optical element withskin of the subject can be included. The patch can include a rigid bodycoupled to the optical element. The rigid body can be configured tostabilize optical path lengths between the optical element and the skin.A plurality of pliable extensions can be coupled to the rigid body. Eachpliable extension can extend away from the rigid body, and can beconfigured to hinder movement of the rigid body relative to the skin. Insome instances, a patch for providing a coupling between an optic and asubject during OCT measurements can have an optical element and amoisture-removing structure configured to contact skin of the subject.The moisture-removing structure can be configured to transport moistureaway from the skin of the subject to hinder moisture build up at aninterface between the optical element and the skin. Moisture removingstructures can include a moisture-absorbent material, and/or aperforated hydrophilic material.

Other embodiments are directed to methods for performing OCTmeasurements to determine an analyte level in tissue, such as a bloodglucose level. Such methods can be implemented without the need to formand/or process an image. An OCT system can be aligned to a subjectthrough an optical coupler. Then a beam can be scanned over a firsttissue site using the attached optical coupler to collect a first set ofOCT measurements. Such scanning can combine light reflected fromscanning a designated tissue site with a reference beam to produce aninterference signal, which can be processed to aid determination of theanalyte level in the tissue. The beam can then be scanned over one ormore other sites to provide corresponding OCT measurements. Each tissuesite can be spatially distinct from the one or more of the other tissuesites. The tissue sites can also form a selected pattern. Scanningwithin a tissue site can include scanning the beam over the entirespatial area of the tissue site and/or scanning to provide data toobtain an analyte level which can reduce the effect of speckle. Aplurality of depths can also be scanned.

Specific sites can be selected from the scanned sites for monitoringanalyte levels, with the corresponding OCT measurements being processedto measure the analyte level in the tissue. The selection of sites caninclude designating whether one or more sites is associated with avalidated site. This can be determine, for example, by determiningwhether corresponding OCT measurements indicate a selected level oftissue hydration. If a two or more sites are validated and correspondedwith a measure of an analyte level, the plurality of levels can beaggregated into an aggregated measure of analyte levels in the tissue,which can be used to calibrate an OCT system. Alternatively, data fromvalidated sites can be used to calibrate an OCT system withoutaggregating the data.

BRIEF DESCRIPTION OF THE DRAWINGS

The present application will be more fully understood from the followingdetailed description taken in conjunction with the accompanying drawings(not necessarily drawn to scale), in which:

FIG. 1 is a schematic diagram of an OCT system, consistent with anembodiment of the present invention;

FIG. 2 is a schematic diagram of a beam scanner implemented to scantissue, according to one embodiment of the present invention;

FIG. 3A is a schematic diagram of a number of tissue sites to be scannedoriented around a circular path, according to one embodiment of thepresent invention;

FIG. 3B is a schematic diagram of a number of tissue sites to be scannedoriented in a gridded pattern to substantially cover a tissue area,according to another embodiment of the present invention;

FIG. 3C is a schematic diagram of the tissue site distribution around acircular pattern overlaid with varying analyte correlating regions,according to some embodiments of the present invention;

FIG. 4 is a cross-sectional perspective view of a beam scanner with ascanning optic, according to one embodiment of the present invention;

FIG. 5 is a cross-sectional perspective view of a beam scanner with atwo scanning optics, according to another embodiment of the presentinvention;

FIG. 6A is a schematic diagram corresponding to locations scanned withina tissue site to substantially scan the tissue site, according to oneembodiment of the present invention;

FIG. 6B is a schematic diagram corresponding to locations scanned withina tissue site to scan a plurality of locations in the tissue site,according to another embodiment of the present invention;

FIG. 7A is a side view of a skin contacting device, consistent with anembodiment of the present invention;

FIG. 7B is a top view of the skin contacting device of FIG. 7A;

FIG. 8 is a schematic of a flow diagram for detecting blood analytelevels in tissue, according to an embodiment of the present invention;

FIG. 9 is a flow diagram of a method for processing OCT measurements,according to an embodiment of the present invention;

FIG. 10 is a flow diagram of a method for determining whether a site isvalid, consistent with one embodiment of the present invention;

FIG. 11 is a flow diagram showing a variety of techniques foraggregating OCT data measurements, according to one embodiment of thepresent invention;

FIG. 12 is a schematic flow diagram of a multi-filtering method fordetecting fluid flow, according to an embodiment of the presentinvention;

FIG. 13 provides graphs of a difference signal from OCT scanning atvarying tissue depths as a function of time, and a corresponding graphof measurements of blood glucose values as a function of time, accordingto some embodiments of the present invention;

FIG. 14 provides a graphs showing overlapping traces of a perfusionsignal and a glucose signal derived from the data shown in FIG. 13; and

FIG. 15 provides a graph of pulsatile blood flow from OCT blood flowmeasurements, according to an embodiment of the present invention.

DETAILED DESCRIPTION

Aspects of the present application that are consistent with someembodiments described herein can improve the use of OCT to determineanalyte levels. The type of analytes that can be identified can includeany analyte capable of being detected with OCT. In many instances, theseanalytes are water-based analytes and/or analytes that are present inblood perfused tissue. Examples include oxygen, hemoglobin, glucose,water, components of blood, and other analytes present in tissues orother samples. In many embodiments herein, glucose is an analyte ofinterest. An analyte correlating region (ACR) is a region of a subject'stissue in which OCT can be applied to provide an accurate estimate of ananalyte's level in the tissue. Accordingly, using OCT to providemeasurements substantially within a ACR can yield data allowing anaccurate estimate of the analyte level.

For a selected analyte, regions of the tissue in which an OCT signal issensitive to changes in the analyte level are not typically uniformlydistributed, either as a function of depth or laterally across thetissue. For example, analytes that are present in blood perfused tissue(e.g., glucose) can be non-uniformly distributed due to the non-uniformdistribution of blood vessels in the tissue. In particular, thepotentially high resolution of OCT, both depth and lateral, enables thelocation of ACRS, for example glucose correlating regions (herein“GCRs”), to be identified. However, since the resolution of anindividual OCT measurement is typically much higher than the scale ofmany ACRS, it can be difficult to insure that these regions will existat a given tissue location which is scanned using conventionaltechniques. Thus, for example, an OCT glucose monitor's performance inthe past has been highly dependent on the location of the skin uponwhich the sensor is placed.

Though OCT can be applied using a brute force technique, analyzing alarge tissue region in depth and extent followed by extensive dataanalysis to isolate portions of the data that do correspond with goodACRS, such a methodology is costly in terms of time and effort expendedto produce accurate analyte level readings. As well, the equipment anddata processing commensurate with such effort can be a financial burden.Accordingly, if one can utilize an OCT technique to quickly identifytissue regions with substantial blood flow, more extensive OCTmeasurements can potentially be performed, and data analyzed, therewithto yield faster and more accurate results. In addition, theidentification of ACRS can be beneficial by reducing the effort neededto utilize OCT to accurately identify an analyte level. Furthermore, ifACRS can be identified more readily, OCT measurements can be lessdependent upon the placement of the sensor vis-à-vis the patient's skinlocation. Some embodiments of the present invention can potentiallyaddress some of these problems. By utilizing embodiments disclosedherein, such as techniques that provide multiple tissue site OCT sensingand/or assessing whether the spots are ACRS, (e.g., by blood flowdetection) an OCT technique can focus data gathering or analysis on theACR regions to collect an analyte level without performing unneeded datacollection and/or analysis on regions which do not correlate analytelevels acceptably.

Other potential advantages can also be accrued. For instance, sensorplacement by the user can be less critical. Since the ACRS within thetissue are not visible to the unaided eye, it is not possible for theuser to place the sensor on a region of tissue that has thesestructures. Further, there are structures within tissue that do notcorrelate with analyte changes, such as sebaceous glands associated withhairs in skin when attempting to sense glucose. In this case again,sebaceous glands are not visible to the user, thus a sensor with theability to monitor multiple tissue sites over a wide spatial extentprovides less sensitivity to sensor placement.

In another instance, monitoring multiple tissue sites potentiallyprovides multiple signals that can be used to improve the sensitivity,stability, and signal-to-noise levels of an OCT system relative to theanalyte changes in the subject.

Also, diversity of tissue sites can provide stability to the OCTsystem's analyte correlation by minimizing the effects of physiologicvariances in a subject during monitoring. An example of this would bechanges in microcirculation on the subject from pharmacologically ortemperature induced changes. In this case, tissue sites where the bloodperfusion changes dramatically (up or down) can identified and weightedby the sites where the perfusion remained more constant generating amore stable output of the sensor.

Systems and Devices for OCT Scanning

Some embodiments are directed to systems for performing OCT to determinethe presence of blood flow in a scanned tissue region. Some additionalembodiments are directed to systems for performing OCT to determine ananalyte level in tissue. Other embodiments combine such detection withother features to perform analyte level estimation with an OCT system.Such embodiments can utilize an OCT system to provide data intensitymeasurements that are analyzed by a processor. Exemplary OCT systems caninclude a number of components such as a light source for generatingskin-penetrating radiation suitable for OCT measurements,interferometers, and/or a detector for receiving reflecting light fromthe skin-penetrating radiation. The system can also include a beamscanner, which can be used to direct a beam of radiation from the sourceto one or more tissue sites. Beam scanners can include devices thatoperate in accord with the disclosure of the present application and/oroperate in a conventional manner. Data collected from one or more of thesites can be processed by a processor to provide a measure of thepresence of blood flow or the measure of analyte levels at therespective sites using any combination of the methodologies disclosedherein and/or known to those skilled in the art. The term “processor” isused generally to include any actual number of devices configured toperform the designated processes. Accordingly, a processor can beembodied as any combination of a programmable unit, a microprocessor, anembedded preprogrammed processor, a stand-alone computing unit, or otherdevices and configurations as understood by those skilled in the art.The system can also include a controller, which can be used to designatea tissue site associated with blood flow or can be used to select one ormore of the multiple sites for further processing (e.g., extractinganalyte data therefrom).

As utilized herein, a tissue site can be a selected tissue region (e.g.,an area or volume of the tissue) which can be probed using OCT. In manyinstances, a tissue site has a geometrical size larger than theresolution of the OCT system. Accordingly, in some instances, the tissuesite is at least large enough to allow an OCT system to perform scanningwithin the site, which can potentially lead to data of an analyte levelwithin the site.

Some exemplary embodiments of OCT systems can be described withreference to the schematic diagram of an OCT system shown in FIG. 1. Alight source 110 is used to generate skin-penetrating radiation 115suitable for OCT measurements. A interferometer is employed to performthe measurement. For example, the interferometer can include a beamsplitter 140 which can direct a measurement light beam 141 to an opticalelement 160 and a reference light beam 142 to a phase shifter 130 (e.g.,a mirror). The sample beam 141 is directed by the optical element 160 toa tissue sample 120 (e.g., a skin portion of a subject). Light 121 isreflected from the tissue 120 and directed to the interferometer. Thereference beam 142 is reflected by the phase shifter 130 back to theinterferometer, where the phase shifter can be positioned to change thephase of the reflected light. The interferometer can combine the lightfrom the phase shifter and tissue sample, and direct the light to adetector 150. The constructively interfered light will provide a signalto the detector 150. Such constructively interfered light thusinterrogates a depth of the tissue 120 selected by the distance traveledby the sample beam 142 to the phase shifter 130. As used herein, tissuedepth is typically the shortest distance from a location in the tissueto a tangent plane on the tissue surface.

In some embodiments where fringe frequency modulation is utilized, thephase shifter 130 is moved at a constant velocity V, which results in afringe frequency proportional to the ratio of V to the wavelength of theradiation. When the sample beam strikes a moving target, this fringefrequency is modulated. Accordingly, some embodiments herein utilize themodulation of the fringe frequency to detect blood flow.

The general use of OCT systems to provide estimates of analyte levels intissues is described in a number of references. For example, U.S. Pat.No. 7,254,429 provides descriptions of methods, devices, and systemswhich can be used to perform OCT measurements in tissue; U.S. PatentApplication Publication No. U.S. 2006/0264719 A1 provides techniques forcalibrating an OCT system for performing analyte measurements; and U.S.Patent Application No. U.S. 2006/0276696 A1 provides techniques forperforming analyte measurements and calibration that include the use ofmultiple wavelengths of radiation. The teachings of each of thesereferences is included herein in their entirety. Accordingly, OCTsystems consistent with embodiments herein can utilize any one orcombination of features of OCT systems described in the referencesherein. For example, in some embodiments, the light source is a lowcoherence source, and/or the system can be specifically configured fordetecting glucose (e.g., blood glucose). OCT systems can be configuredas non-imaging systems, which can optionally allow scanning of a tissuesite such as to reduce the effect of speckle. In another example, thelight source of an OCT system can utilize one or more wavelengths toenable glucose reading detection. Other aspects of OCT systems that canbe utilized with embodiments herein can include features understood bythose skilled in the art.

Beam Scanners and Controllers

Some embodiments herein include a beam scanner which can be configuredto direct beams of radiation to one or more tissue sites for an OCTsystem. Such beam directing can be achieved in a variety of manners. Forinstance, as shown in FIG. 1, a beam scanner 170 can be coupled to oneor more optical elements 160 to direct the beam to a particular site. Abeam scanner, however, can also be coupled to any combination of opticsand/or other light directing devices to provide the scanning. Forexample, the beam splitter, optionally in conjunction with one or moreother optical elements, can also be coupled to the beam scanner suchthat the scanner can direct scanning of light impinging on a sampleregion. A controller 175 can also be included. The controller, which canbe coupled to the beam scanner, can be used to facilitate operation ofthe beam scanner in a variety of manners (e.g., identify and/or directwhich tissue sites should be utilized to provide an analytemeasurement). A controller can be an integral portion of a beam scanner(e.g., within the inner workings of a single device) or can be embodiedseparately (e.g., as a processor of a microcomputer which is inelectrical communication with a beam scanner). It should be understoodthat a beam scanner coupled with a controller can be part of an OCTsystem, or alternatively constitute an embodiment by itself.

The imaging optics of a beam scanner can be configured to have a varietyof characteristics. First the optics can be configured to reducevariations in focal depth during the scanning at widely differingspatial positions. Also, the optical train of a beam scanner can beconfigured to limit unwanted spurious reflections that can corrupt theinterferometer signal such as from optical surfaces at criticalpositions in the optical path. The numerical aperture of the optics canbe selected to reduce the returned scattering signal while minimizingthe confocal effect through the depth of interest in the skin.Aberrations due to far off axis scanning through the optic can also bedesirably reduced.

Beam scanners can be configured to scan one or more tissue sites wherethe distinction between sites and the spatial extent of a particulartissue site can also be varied. For instance, each site can be chosen tohave a unique region relative to every other site (i.e., none of thesites overlap). The sites can substantially cover a tissue section to beinvestigated, or can be distributed within a tissue section with spacetherebetween. The sites can form a selected pattern or can be randomlydistributed therein. In some embodiments, the sites can be spacedfarther apart than some characteristic length scale of an ACR. Suchembodiments can allow an OCT system to quickly assess a tissue sample tolocate ACRS where further measurements can be taken and/or analysis ofparticular measurements is to be performed to reduce the effort of datagathering and analysis. The characteristic length scale of an ACR candepend upon the analyte to be estimated and/or the type of tissue to bescanned. For example, with glucose correlating regions (GCRs), thecharacteristic length scale can be on a length associated with thedistribution of blood vessels in a dermal region.

The spatial extent of a tissue site can also selected in a variety ofgeometries. For instance, different tissue sites can be distributed overa certain area with all the sites being substantially at the same depth.In other situations, the tissue sites can span a variety of depthsand/or spatial extents, encompassing various volumes.

With regard to the size of a tissue site, as mentioned earlier, eachtissue site can be a tissue region large enough that an OCT system canprobe a variety of locations in the tissue site to determine an analytelevel in the region (e.g., the region can be large enough so thatanalyte correlation in the region is possible). As well, the tissue sitecan be a region large enough to encompass an ACR, or to perform someother functionality associated with analyte detection (e.g., largeenough to allow scanning therein to reduce speckle in an OCT system inwhich an analyte level is being estimated as described in U.S. Pat. No.7,254,429). The tissue site can also be limited in size such thatscanning in the site can be relatively rapid vis-à-vis scanning theentire area covered by a plurality of sites. The tissue size can also belimited such that such that the effects of structures that do not changewith an analyte (such as a hair on glucose sensing) on one tissue sitedoes not influence the signal received in another tissue site. Therelative sizes each of the tissue sites can also vary, or besubstantially uniform.

As well, the beam scanning can be performed using various dataacquisition techniques to provide OCT data that can be used for avariety of purposes. For example, the scanning within a tissue samplecan be sufficient to provide data allowing an analyte level measurementwithin the tissue sample. In another example, the scanning can providedata that allow validation of a site, as described herein, to determinewhether a tissue site is an ACR which can provide good analyte levelestimation. For instance, validation of a site can depend upon detectingthe presence of blood flow. The latter example, can potentially lead toa more rapid data collection methodology where sites can initially bescanned for validation—and the validated sites are rescanned to providemore detailed OCT data for analyte level measurements within eachvalidated site. Other varieties of scanning within a tissue site arealso contemplated.

In some embodiments, beam scanners for use with OCT systems can adjustmovement of a beam over multiple length scales, e.g., at least twodifferent length scales. For instance, the beam scanner can move a beamover a site-scale, where the beam is moved over a distance large enoughthat the beam scanner probes a plurality of tissue sites within thedistance of a coarse scale (e.g., site scale). Accordingly, the beam caninterrogate a multiplicity of tissue sites (e.g., non-overlapping sites,and/or sites separated by a distance larger than a characteristic lengthof an ACR). The beam scanner can also be configured to move the beamover a measurement scale. Typically, the measurement scale is smallerthan the coarse scale. OCT measurements can be taken within themeasurement scale to provide an analyte level estimate in the tissue(e.g., the measurement scale has a size sufficient to allow analytemeasurement correlation). It is understood that scanning over a coarsescale can incorporate any of the features regarding different tissuesites (e.g., the site-scale scans over tissue sites that do overlap oneanother), while scanning over the measurement scale can incorporate anyof the features described herein regarding scanning within a tissue site(e.g., scanning in a tissue site to reduce speckle from a compositesignal). It is understood that scanning can also be performed overadditional length scales as well.

Some illustrations of features previously described with respect to beamscanners are described with reference to FIGS. 2 and 3A-3C. FIG. 2provides an illustration of some features of particular embodiments ofthe present invention which utilize a beam scanner. The scanner 210 cancomprise a body of a device with one or more optics 261, 262. The optics261, 262 can be configured to direct light from an interferometer 240 toan imaging optic 263, which further directs the light to tissue 250. Byconfiguring the optics 261, 262 appropriately, a beam that impinges upontissue can be manipulated to provide multispot scanning. For example,one optic 261 can position the beam over multiple tissue sites, whileanother optic 262 can provide scanning within a tissue site, which canprovide data for analyte measurements. Alternatively, a single optic canprovide both the coarse and fine scanning functions (e.g., a galvanicreflecting mirror driven for large scale beam displacements in thecoarse tuning mode and fine dithering in the analytic mode).

FIGS. 3A-3C provide some exemplary orientations for tissue sites whichcan be scanned with an OCT device. As shown in FIG. 3A, a beam scannercan be configured to distribute tissue sites to be scanned around acircular path. The beam scanner can thus move the beam around a diameter13 to distribute tissue sites therearound. As well, the beam scanner canmove an OCT beam within a length scale 23 to provide OCT measurementswhich can be correlated to an ACR potentially. FIG. 3B presents anotherpattern of tissue sites that can be scanned with an exemplary beamscanner. The tissue section 310 can be gridded into a set of adjacentsites 311 that substantially cover the tissue section 310. Accordingly,a beam scanner can be configured to move the beam such that tissue sitesare distributed over a length scale 14, while each tissue site isinterrogated on a smaller length scale 24. It is understood that for anytissue site pattern, the number of tissue sites to be distributed, theshape of the pattern on which tissue sites are distributed, and thescanning within the tissue site can all be varied. For example, thetissue site need not be square shaped, and the entire tissue site neednot be interrogated to obtain data for OCT scanning.

FIG. 3C schematically depicts a tissue site 325, 326, 327, 328distribution pattern to be interrogated by a beam scanner overlaid withthe analyte correlating regions 330, 331, 332 of a tissue sample 320. Asdepicted, some tissue sites 325, 326, 328 intersection portions of ACRS330, 332, 331, while one tissue site 327 does not interrogate an ACR.Accordingly, by identifying the tissue sites that intersect ACRS, a moretargeted analysis and gathering of OCT data can be performed to obtainanalyte levels in the tissue 320.

FIGS. 4 and 5 depict embodiments of beam scanners that have been reducedto practice. FIG. 4 depicts a beam scanner 400 which utilizes twodiscrete optical elements. One optical element can locate tissue sitesby utilizing a rotating wedge prism 410, which can displace the tissuesites around a circle, as depicted in FIGS. 3A and 3C. The other opticalelement can provide the scanning within a tissue site (e.g., rasterscanning). This element can be embodied as a moveable mirror, forexample a mirror coupled to a flexure. The flexure can be attached toelectromagnetic coils to affect its positioning of the mirror, whichallows scanning within the tissue site.

FIG. 5 depicts another embodiment of a beam scanner, which utilizes asingle optical element for beam steering. The optical element is coupledto a flexure, where the flexure is configured to move the optic (e.g., amirror) with a greater deflection angle, relative to the flexure used inthe device shown in FIG. 4. In this particular flexure, all positions ofwithin a selected spatial extent are scannable, akin to what is shown inFIG. 3B. Accordingly, a greater variation in designation of tissuesites, and scanning within tissue sites, can be achieved with thisdesign. It is understood that other beam scanners can utilize any numberof optical elements and/or devices to manipulate the optical elements,in a manner consistent with the functionality of the described devices,including using such elements within the knowledge of one skilled in theart.

With regard to scanning within a tissue site, beam scanners can beconfigured to perform such scanning using various methodologies. Thescanning can be sufficient to substantially cover an entirety of atissue site as shown in FIG. 6A, or can scan a variety of locations inthe tissue site that are spaced apart. For instance, the scanning can besuch that enough locations are scanned in a manner to allow reduction ofspeckle when the OCT measurements are combined to estimate an analytelevel. In some embodiments, a raster scan is performed within the tissuesite. The raster scanning can be performed in any designated pattern,with as many or few locations actually probed as desired; one example isshown in FIG. 6B. For example, the raster scanning can be of an area, aline, or a volume of locations. In many instances, the raster scanningis done at a plurality of depths of tissue.

As discussed earlier, a controller can be incorporated with an OCTsystem and/or a beam scanner to aid in the scanner's operation. Forexample, a controller can be used to associate each of a plurality oftissue sites with particular OCT measurements taken therefrom. The OCTmeasurements can be used to estimate selected analyte levels therefrom,or can be used to “validate” the site for estimating selected analytelevels (e.g., using the data to determine whether the site covers asufficient amount of an ACR to extract analyte level data therefrom). Insome embodiments, the controller can select the tissue sites (e.g., thevalidated tissue sites) that will be interrogated in further detail, forinstance taking further OCT measurements to determine analyte levelsfrom data taken therefrom. Alternatively, if data for determininganalyte levels has been extracted from a set of tissue sites previously,the controller can act to determine which tissue site(s) should beexamined to determine analyte levels.

Validation of a tissue site for OCT analyte measurement can be performedusing any number of techniques including those known to one skilled inthe art for analyzing OCT data. Some embodiments utilize OCT measures oftissue hydration as a technique for validating a tissue site. When ananalyte is associated with the level of hydration in a tissue sample(e.g., the amount of blood perfused tissue), one measure of whether thesite encompasses an ACR is a measure of the hydration level in thetissue. As discussed in U.S. Pat. No. 7,254,429 and U.S. PatentApplication Publication No. U.S. 2006/0276696 A1, a section of tissuecan be scanned at two wavelengths, one wavelength that has a lowabsorption coefficient for water/blood components and a high scatteringcoefficient for such components (e.g., 1310 nm), and one wavelength thathas a high absorption coefficient for the water/blood components (e.g.,1450 nm). By comparing the intensity of backscattered light over atissue sample at each of these components, one can establish a measureof hydration in the tissue sample. For example, the difference in theaverage intensity level of OCT backscattering of a tissue site betweentwo wavelengths can be calculated and serve as a validation metric. Whenthe average difference exceeds some threshold value, the site can bedesignated “valid,” while a measure below the threshold value can bedesignated “not valid.” Since the average intensity value depends uponthe spatially distributed backscattering intensity, validation of atissue site can also depend upon the extent to which an ACR overlaps theinterrogated tissue site. Referring back to FIG. 3C, a tissue site 327which does not intersect an ACR will have a low difference value. Tissuesites 325, 326, 328 that intersect an ACR will provide a differencevalue that depends not only on the analyte level in the ACR but therelative overlap of the ACR with the tissue site. Accordingly, onetissue site 326 can exhibit a higher difference value that other tissuesites 325, 328 that intersect ACRS even if all the ACRS have the sameanalyte levels therein. Variations on such techniques are also includedwithin the scope of the present application. For example, validation ofa tissue site can be performed by examining OCT data taken at twodifferent wavelengths where the wavelengths are selected to provide acontrasting signal indicative of the presence of a particular analyte,for example oxygenated hemoglobin vis-à-vis deoxygenated hemoglobin asdiscussed in U.S. Patent Application Publication No. U.S. 2005/0059868A1. It is also understood that combinations of validation techniques canbe implemented to provide tissue site validation.

Some embodiments are directed to beam scanners and/or controllers thatare configured to validate and/or select a site based upon an OCTmeasurement indicating the presence of blood flow. The measure of bloodflow can be identified in a variety of ways, as described within thepresent application. Accordingly, embodiments of the invention aredirected to devices (e.g., OCT systems, beam scanner, and/orcontrollers) that are configured to detect fluid flow (e.g., blood flow)using any combination of the techniques discussed herein. Such bloodflow can be associated with an analyte, and therefore the validatedtissue site with blood flow can be subjected to further OCT measurementsand/or data analysis to extract analyte levels.

As previously mentioned, validated tissue site(s) can be interrogatedand/or data analyzed therefrom to associate a corresponding analytelevel therewith. In some instances, a controller can aggregate theanalyte levels from two or more validated sites to provide an aggregatedmeasure of the analyte level in the tissue. Such aggregation can be anaverage value, a median value, or other aggregated value as understoodby one skilled in the art; some further aspects of how aggregation canoccur, and thus be implemented in a controller, are discussed herein.Alternatively, or additionally, the analyte levels corresponding withone or more validated sites can be used to calibrate an OCT system suchthat future OCT measurements utilize the calibration. Such calibrationcan utilize any of the techniques described in U.S. Patent ApplicationPublication Nos. U.S. 2006/0264719 A1 and U.S. 2006/0276696 A1.

Optic/Skin Contacting Devices

Some embodiments of the present invention are directed to a structurefor coupling an optic to a subject, which is configured for use with anOCT measurement. Some exemplary embodiments include the structureitself, an OCT system with such a structure, or a patch. Embodiments caninclude one or more features as described herein. Such couplingstructures can be configured to reduce mechanical distortion of the skinat a measuring site. The distortion includes two types. First, the localdistortion of the skin due to the protrusion of the optic surface intothe skin. Reducing this effect can hinder longer term stretching and/orthe need to accommodate a continuous change in the baseline signal dueto the stretching. Such changes, referred to as settling, are notcorrelated with analyte changes and represent the viscoelastic responseof the skin to the pressure of the optic. At the same time, however,protrusion of the optic can be desirable to insure stable continuouscontact of the measuring surface with the skin under all conditions offorce on the sensor or assembly. The second category of distortion isdue to forces on the sensor such as sensor weight, inertia duringmovement, or brushing the sensor against an object. Also, a sensor cablecan transmit some force to the assembly in the form of a torque or apull, causing motion that deforms the skin macroscopically over thedisposable attachment region. Examples are a twisting of the skin thatmay rearrange the analyte correlating structures in depth, or a pullthat due to the varying modulus of the features in the skin causes achange to the baseline interferometer signal.

Some exemplary embodiments are directed to a structure for coupling anoptic to a subject that include one or more optical elements that can becoupled to an OCT system to guide reflect light from skin. Oneparticular embodiment is shown in FIGS. 7A and 7B. An optic 740 caninclude a protruding portion 745 for contacting the skin of a subject. Apatch can be used to align the optical element on the subject's skin.The patch can include a rigid body 720 coupled to the optical element740 to stabilize the optical path lengths between the element and theskin. The optical element 740 can optionally be removably couplable withthe rigid element. Accordingly, in some embodiments, the patch sectioncan be configured as a disposable element, with the optic beingreusable. The patch can further include a plurality of pliableextensions 710 coupled to the rigid body 720. Each extension can beconfigured to extend away from the rigid body, and configured to hindermovement of the rigid body relative to the skin. Extensions can beconstructed with any suitable material having a flexible quality;non-limiting examples include polymer-based materials that canoptionally have elastic qualities. Adhesive 730 can be applied to couplethe structure to the skin. It is understood that the preciseconfiguration of such a structure as shown in FIGS. 7A and 7B does notlimit the scope of such structures.

Other embodiments are directed to a optic-skin interface that can helpremove moisture from the interface. If moisture from the skin is allowedto build up at the interface, the optical interface to the skin can bedistorted and the characteristic shape of the baseline scan can change.Accordingly, one exemplary embodiment is directed to a patch for OCTmeasurements that includes an optical element and a moisture removingstructure 750 as shown in FIG. 7A; it is understood that the moistureremoving structure need not be incorporated with all the exact featuresdepicted in FIG. 7A. The moisture removing structure can be configuredto transport moisture away from the skin to hinder moisture build up atthe interface between the optical element ad the skin. The moistureremoving structure can utilize any number of moisture-absorbentmaterials and/or hydrophilic materials. For example, a hydrophilic foamcan be used which allows moisture to be removed by capillary action fromthe skin and transported to an exterior surface of the foam forevaporation to the external environment. A moisture removing structurecan also be embodied as a perforated structure around the optic, whichcan allow moisture to evaporate directly through the perforations.

It is understood that other features for coupling OCT optics to asubject can also be incorporated within the scope of the presentinvention. Some of the these features are described in U.S. PatentApplication Publication No. U.S. 2007/0219437 A1.

Methods of Estimating Analyte Levels Using OCT

Some embodiments are directed to methods of determining or estimatinganalyte levels in a tissue using OCT measurements. These methods can bepracticed using any number of devices including any appropriatecombination of the devices revealed in the present application. However,it is understood that such methods can also be implemented using otherdevices, including those known to one skilled in the art, albeitspecifically configured to practice the embodied method. Accordingly,these methods are not limited by the specific devices, and theirdelineated operation, revealed elsewhere in the present application.Likewise, the methods described herein, and portions thereof, can beimplemented on devices described in the present application.Accordingly, some devices, such as a beam scanner and/or controller, canbe configured to carry out portions or the entirety of a methodconsistent with some embodiments of the present application.

Some embodiments of methods for estimating analyte levels in tissue areconsistent with the flow diagram depicted in FIG. 8. One or more tissuesites can be scanned using OCT 810. Scanning can occur over atwo-dimensional region (e.g., at a specified depth), or can be scanningover a volumetric region (e.g., scanning a designated area at amultiplicity of depths). A tissue site can be defined as discussed withrespect to beam scanners herein. For example, the tissue site can bespatially distinct from any other (e.g., not overlapping), and/or can bespaced apart from one another. Next, the data collected from thescanning can be analyzed to determine whether blood flow is present inthe corresponding tissue site 820. The data can correspond withbackscattered light from the OCT measurements, which can potentiallycarry information about the presence of blood flow. Finally, a measureof a blood analyte level can be obtained from one or more of the tissuesites that exhibits blood flow from the analyzed data 830. Measurementcan include the steps of obtaining OCT data from the sites where bloodflow is present to obtain data sufficient to estimate an analyte level,and/or analyzing pre-obtained OCT data in a manner to extract analytelevels.

Some embodiments of methods for estimating analyte levels in tissue areconsistent with the flow diagram depicted in FIG. 9. An OCT system canbe aligned using an optical coupler to a subject 910. For instance, acoupling can be attached to a subject through which light is transmittedand reflected to obtain OCT measurements.

A plurality of tissue sites (e.g., at least two) can be scanned usingthe optical coupler 920. Scanning can occur over a two-dimensionalregion (e.g., at a specified depth,) or can be scanning over avolumetric region (e.g., scanning a designated area at a multiplicity ofdepths). The tissue sites can be defined as discussed with respect tobeam scanners herein. For example, the tissue sites can be spatiallydistinct from one another (e.g., not overlapping), or can be spacedapart using some characteristic length scale, as discussed earlier. Asdiscussed earlier, any combination of the OCT measurement techniquesdiscussed by the references disclosed herein, or as utilized byembodiments including a beam scanner as discussed herein, can beutilized to perform the scanning step. In one example, the entirety orportions of a tissue can be scanned as depicted in the selected patternsof FIGS. 3A and 3B, or any other selected pattern. As well, within atissue site the entirety or a portion of the tissue site can be scanned.In another example, scanning can be performed within a tissue site toprovide an OCT measure of an analyte level that is reduced in specklecontent and/or is oriented toward a non-imaging technique. Scanning of atissue site can be performed to render a variety of data types as well.For example, the scanning can provide data that can be converted to anestimate of analyte levels, and/or the scanning can provide data thatallows validation of a tissue site as described in the presentapplication.

One or more of the scanned tissue sites can be selected 930 for furtherprocessing. Such selection can be performed either after scanning of alltissue sites is completed, or at any time after a particular tissue sitehas been scanned. In some embodiments, a survey of tissue sites can beinitially scanned to determine which will be selected for OCT analyteestimation processing.

Alternatively, or in addition, sites can be investigated in an on-goingmanner (e.g., after a selected number of interrogations for analytelevel estimation on a cyclic basis) to continue to validate that thetissue site is appropriate for analyte level estimation. Such on-goingselection of tissue sites can act to monitor the potential perturbationsand/or physiologic drift that can occur in tissue to alter the locationof an ACR. Use of an on-going site selection monitoring technique canresult in an adaptive technique that helps maintain the accuracy of ananalyte level estimator. In some embodiments, the selection is performedby validating the tissue site using any of the variations discussedwithin the present application (e.g., using a measure of tissuehydration level, or using a multiple wavelength measuring technique thathighlights the presence or absence of a selected analyte).

OCT measurements at the selected tissue sites can be processed toestimate analyte levels 940. For example, processing can include usingdata at validated sites to calibrate an OCT sensor. Such calibration canbe as previously mentioned in the present application. In anotherexample, when more than one site has been selected (e.g., validated)analyte levels corresponding with each of the validated sites can beaggregated to provide an aggregated measure of the analyte level in atissue. Aggregation can also include aggregating all the data associatedwith selected tissue sites at once without determining an individualanalyte level estimate for each tissue site. Aggregation can beperformed in a variety of manners. Some non-limiting examples include:simple or trimmed mean/median of all signals, weighted averaging basedon signal properties, weighted averaging based on input from the siteselection algorithm, or some kind of cross-correlation/convolution ofthe signals.

FIG. 10 provides one example of a method for performing site selection.Scans (e.g., depth scans) are performed for a number of tissue sites,with depths being probed by a raster scan 1010. Next, site metrics areapplied 1020 to determine if a site is acceptable. Such site metrics caninclude site validation determination using OCT scans at differentwavelengths of light to characterize tissue. If a site is acceptable1030, 1040, its OCT measurements can be used to identify an analytelevel, such as by using its measurements in an aggregation algorithmwith other acceptable site data. If the site is not validated 1030, 1050it can be considered unacceptable for measuring analyte levels. It isunderstood that site that are designated unacceptable may be acceptableat later times, for example when implementing an on-going validationsite methodology.

Aggregation can take place at several points in the data process asexemplified in the flow diagram of FIG. 11: First, depth scans can becollected 1110 from raster scanning a number of tissue sites. In oneinstance, the individual depth scans can be validated using a siteselection algorithm 1120, 1121, 1122 with the selected sites beingaggregate to form a base scan 1130. An analyte converting technique(e.g., glucose conversion technique 1140) can be applied to theaggregated base scan to form an analyte level measure, which cansubsequently be used to calibrate an OCT system 1170. In anotherinstance, the individual depth scans can be averaged to formcorresponding base scans 1150. The base scans can each be subjected to asite selection algorithm 1121 to determine which are valid. The validscans can then be further analyzed to report analyte levels forcalibration of an OCT system. The analyte levels for corresponding toeach valid site can be aggregated 1180, or the OCT data of the validsites can first be combined into a single scan 1160 before the analytelevel is determined for the base scan.

Fluid flow detection using OCT can be achieved using a variety ofmethodologies. One methodology involves detecting changes in a specklepattern indicative of the presence of fluid flow. In many instances,each raw OCT scan can exhibit a high degree of speckle in the signal dueto the micro-roughness of the skin and the coherence of the opticalsource. Some aspects of this effect are described in U.S. Pat. No.7,254,429. This speckle “noise” on the underlying depth intensity signalis a function of the optical coherence length, wavelength, distance fromthe focal point, size and shape of the scattering centers, and opticalproperties of the scatterers and the surrounding media. In speckleflowometry, the particles in the flowing fluid (e.g., red blood cells inblood) can cause the speckle pattern in the region of the flow to changein time more rapidly relative to the change in the speckle of thesurrounding tissue. Tissue sites with a high degree of speckle temporalvariations are sites where blood flow exists. Thus, when an bloodanalyte (e.g., blood glucose) is sought to be identified, the presenceof blood flow can correspond with the presence of an ACR.

Accordingly, some embodiments are directed to techniques that utilizeOCT intensity data measurements that exhibit speckle. The speckle inthese measurements can be analyzed to determine whether blood flow ispresent, for example by comparing two or more different intensity datameasurements. Comparison of intensity data measurements for speckledifferences can occur in a number of ways. In one instance, two or morescans at one location at a particular tissue depth are repeated atdifferent moments in time (e.g., over a time period of less than about afew seconds). Comparison of the corresponding intensity data sets canindicate the presence of fluid flow if the changes in speckle aresubstantial. If this is also performed at varying depths, providingintensity data sets of a set of locations at different times and depths,comparison of the intensity sets can also indicate where blood flow ismore of less prevalent depending upon the relative temporal changes inthe speckle pattern as different times (e.g., more change correspondingwith more flow). It is understood that more than one location couldpotentially be scanned, with the trade-off of requiring more time tocomplete which can complicate a temporal analysis.

In another instance, a set of scans (e.g., raster scans) is performed ata variety of locations (e.g., linear raster scans) at varying depths.The depths that are more similar to one another in speckle pattern canbe indicative of less blood perfused tissue, while depths that differ inspeckle pattern can be more indicative of the presence of blood perfusedtissue. This technique can potentially require less data than theformerly described technique, but with a trade off of signal to noiseratio.

Another methodology for detecting fluid flow using OCT relies ontechniques associated with Doppler OCT, or more particularly inexamining the frequency modulation in an OCT fringe signal due to theinteraction with fluid flow. As mentioned earlier, when the phaseshifter in a reference arm of an OCT system moves at a constantvelocity, a corresponding fringe frequency is established. In fringefrequency modulation, moving particles in a flowing fluid can cause ashift in the observed frequency of the interferogram in the region ofthe blood flow. Accordingly, this technique utilizes some principleslike what is exploited in ultrasonic imaging of blood flow. Previouswork in Doppler flowometry has adopted this technique for OCT, andrelies on analyzing the shift in the peak frequency. Examples of suchwork include Zvyagin, et al., “Real-time detection technique for Doppleroptical coherence tomography,” Optics Letters, Vol. 25, No. 22, Nov. 15,2000, pp. 1645-47; Davé et al., “Doppler-angle measurement in highlyscattering media,” Optics Letters, Vol. 25, No. 20, Oct. 15, 2000, pp.1523-25; Zhao et al., “Doppler standard deviation imaging for clinicalmonitoring of in vivo human skin blood flow,” Optics Letters, Vol. 25,No. 18, Sep. 15, 2000, pp. 1358-60; Zhao et al., “Real-timephase-resolved functional optical coherence tomography by use of opticalHilbert transformation,” Optics Letters, Vol. 27, No. 2, Jan. 15, 2002,pp. 98-100; Barton et al., “Flow measurement without phase informationin optical coherence tomography images,” Optics Express, Vol. 13, No.14, Jul. 11, 2005, pp. 5234-39. Doppler flowometry can be very sensitiveto orientation of the flow relative to the incoming beam from the OCTsensor which provides a challenge in extracting quantitative blood flowmeasurements.

Accordingly, some embodiments are directed to techniques for detectingfluid flow (e.g., blood flow) by scanning one or more tissue sites tocollect fringe modulated data and analyzing the fringe modulated datafor the presence of blood flow in the tissue site. Such measurements canbe made at varying depths, which can allow the fringe frequency to bedetermined.

Determination of the presence of fluid flow can be achieved in a varietyof manners. A shift in fringe frequency components (e.g., shift in thepeak fringe frequency) relative to what is expected from a moving phaseshifter can indicate the presence of fluid flow. Using other techniquesknown to those skilled in the art, further data can be extractedincluding directionality of the scatterers and a velocity profile. Suchdetailed information, however, can require substantial data processing.Accordingly, some embodiments utilize a digital signal processing toextract the shift in a peak frequency. For example, when a phase shifteris configured to provide a 600 kHz baseline signal, oversampling by afactor of 5 or more will typically utilize a 3 Msps system with at least12 bits of data conversion resolution.

Some embodiments are directed to techniques that examine the amplitudemodulation of an OCT signal (e.g., vis-à-vis a tissue sample with nofluid flow) to determine if fluid flow is present. Amplitude modulationis distinct from looking at the shift in the peak fringe frequency, andcan include such observables as the examining the intensity changes atselected frequencies, the frequency broadening, and/or a shape change ina fringe-frequency envelope. For instance, the backscattered OCT signalcan be examined for a change in total intensity of the signal (e.g.,over a given bandwidth), and/or a measure of the broadening of thefringe-frequency envelope relative to the initial OCT signal. As an OCTbeam interacts with moving particles, not only does the main frequencyshift due to the movement but the breadth of the frequency componentscan also grow. Without necessarily being bound by any particular theory,it is believed that speckle plays a role in frequency broadening. Sincespeckle has a tendency to create high frequency components in the data,such components are more likely to be shifted by interaction withscatterers. Accordingly, detection of the amplitude modulation of theenvelope of frequencies can be an indicator of the presence of fluidflow. For example, digital signal processing can be applied to abackscattered signal to create a measure of the amplitude modulation(e.g., looking at a measure of the shape change in the envelope relativeto what is expected for tissue without fluid flow or relative to aninitial signal).

In some embodiments, examination of the amplitude modulation can alsoallow the use of less data intensive techniques for signal processingrelative to known techniques that follow the Doppler shift in a peakfrequency. If properties such as directionality and relative velocityare not to be determined, simpler signal processing techniques (e.g.,analog signal processing) can be utilized, though more advanced dataprocessing is not precluded. For instance, the integrated power of aninterferogram can be examined to determine the presence of fluid flow.Thus, detection of the envelop shape of a return signal, relative to anexpected shape, can be enough to determine the presence of fluid flow.Thus even though directionality information is lost, an indication offluid flow is more easily identified with less data processing. It isunderstood, however, that techniques susceptible to use with analogsignal processing can also substitute digital signal processing,consistent with some embodiments of the present invention.

For instance, in some embodiments, a backscattered wide band signal froman OCT system is filtered to determine the presence of fluid flow. Thefiltered signal of a backscattered wide band signal can be used, in someembodiments, to produce a filtered signal indicating fringe frequencymodulation indicative of blood flow's presence. Such a system canutilize either analog or digital signal filtering. One filter applied tothe backscattered signal can be a narrow band filter, which can becentered at the base fringe frequency set by the phase shifter. Thewidth of the filter frequencies can be chosen such that the filteredbackscattered signal is indicative of the presences of fluid flow. Forexample, the filtered backscattered signal from tissue with little to nofluid flow has substantially higher intensity than the filteredbackscattered signal from tissue with fluid flow present. Accordingly,in some situations, the bandwidth of the narrow band filter can act toreduce the intensity of a backscattered OCT signal by eliminating higherand lower frequency components that shift out of the bandwidth due tothe presence of fluid flow.

Another filter can also be applied to the raw backscattered OCT signal,where this filter is a wide band filter, relative to the narrow bandfilter, which can also be centered at the base fringe frequency set bythe phase shifter. The wide band filter can be configured with abandwidth such that a portion of backscattered OCT signal, whenscattering is from tissue having fluid flow present, is still in thefiltered signal (e.g., at least one fringe-modulated feature).Accordingly, comparing the intensity data from the wideband filteroutput and the narrow band filter output can be indicative of thepresence of fluid flow. In particular, the use of the wide band filtercan act to allow adjustments due to tissue movement or other changes notdue to detecting fluid flow, thus decreasing the possibility of falsepositives.

It is understood that digital or analog filters for amplitude modulationexamination can have a number of other configurations that differ fromwhat has just been described. For example, a filter need not besymmetric about a centered frequency, and/or the filter need not becentered at the frequency of the initial fringe-frequency. Indeed, thefilter(s) can be chosen in any suitable manner to accentuateidentification of amplitude modulation to aid fluid flow determination.

One exemplary embodiment of the use of a multifiltered backscattered OCTsignal system for fluid flow detection is shown in FIG. 12. Abackscattered signal can be received from reflected light from thetissue of a subject interrogated using an OCT system. The OCT system canutilize a base phase fringe signal having a frequency of around 600 kHzcentered. The wide band output of an optical receiver 1210 that acceptsthe reflected light can be routed through at least two filter channels.The narrowband channel contains a narrow band pass filter 1222, centeredon the original fringe rate of the interferometer. The filtered signalis then integrated 1232 and passed through a data acquisition board(DAQ) 1242 to be further processed by a computer 1270 (e.g., forobtaining glucose level estimations). The narrow filter signal can beused to compute structural changes induced by glucose variations. As aside effect, this filter 1222 will reduce the contribution of scatteringby blood and blood related components as Doppler induced shift from theblood flow will move the signal outside of the filter band pass.

The wideband channel of FIG. 12 passes the backscattered OCT signalthrough a wide band pass filter 1221 which is also centered at theoriginal fringe rate of the interferometer. The wide band filteredsignal is also integrated 1231 and then digitized by the DAQ 1241. Thewideband channel contains higher or lower additional frequencycomponents of the signal. Due to the Doppler shift and spectralbroadening generated by the passing blood cells, the wide band signalwill increase relative to the narrow band one whenever flowing blood isencountered. Differences between these narrow band and wide bandsignals, as determined by a comparitor 1250 for example, can then beused as indicators of the depth and magnitude of blood flow. Anindication of the blood perfusion in the scanned tissue 1260 can then beprovided. While the directional information is lost with this technique,the simplicity of implementation, and the natural conversion speed ofanalog processing make such an embodiment potentially useful.

As mentioned earlier, the use of amplitude modulation in an OCT signalto detect fluid flow can also utilize analysis of the speckle in thebackscattered OCT signal. For instance, the multi filter approachdescribed above can also be applied to the speckle analysis. Since anarrow band filter can be configured to reduce the intensity of theobserved speckle due to fringe frequency shifting, the variance of thespeckle can also be lower. Thus, the speckle variance of the resultingOCT signals from the two filters can be compared to identify adifference in the speckle variance in space, in time, or both.

OCT identification of blood flow in a tissue can be used in a number ofways. As alluded to earlier, blood flow identification can provide ameasure of blood perfusion in tissue, which can identify whether atissue section exhibits characteristics for analyte level estimation(e.g., identifying that the tissue has an ACR at a particular set oflocations such as at particular depths or lateral extents). The bloodflow identification can also serve as an indicator of heart rate bychoosing an blood flow location and monitoring the signal's sinusoidalbehavior, correlating the oscillatory behavior with heart rate. In someembodiments, during an analyte monitoring session, these blood flowidentification techniques can also provide a timely indication ofsignificant sensor disturbance (i.e., the loss of a signal indicatingthe presence of blood flow), which otherwise may render the analytemeasurement inaccurate.

EXAMPLE EMBODIMENTS

The following example is provided to illustrate some embodiments of theinvention. The example is not intended to limit the scope of anyparticular embodiment(s) utilized.

An OCT system was implemented to carry out the method diagrammed in FIG.12 using commercially available equipment.

A test is carried out at a specific tissue site. An initial OCT scan ofthe tissue at varying depths is performed. The data over each depth isaveraged to give an averaged intensity data at that point. Subsequently,OCT scans of the same tissue site are performed at varying moments intime, each of which is designated by a scan number in FIG. 13. Theaveraged value of the OCT scan versus depth for each time was subtractedfrom the initial OCT averaged scan value versus depth. The differencesare plotted in the pixel plot shown in the top portion of FIG. 13, wherea measure of the difference is provided by the shading of the pixel. Thelower portion of FIG. 13 provides a corresponding time graph of measuredglucose values in the blood stream of the subject whose tissue wasscanned. Accordingly, the comparison of the two plots shows that the OCTmethod can identify regions of tissue that are susceptible to change dueto glucose and the presence of blood flow.

FIG. 14 aggregates the pixel data of FIG. 13 by summing all thedifference data at a given depth location over all times. That summationis plotted as a function of depth to provide an indicator of the glucosesignal, which is the thick line shown in FIG. 14. The data is normalizedon the maximum summation in the data set. The thin line corresponds to aperfusion signal measure obtained using the signal processingexemplified in FIG. 12. The backscattered data from a scanned tissuesample at a given depth was sent through a wide band filter and a narrowband filter. An integrator aggregated the data. The differences betweenthe filter outputs at varying depths was plotted as shown by the thinline of FIG. 14. Again, the data is normalized on the maximum differencevalue. The correspondence between the lines as a function of time showsthat a measure of tissue perfusion can act to identify glucosedistortion regions, and can provide a glucose independent site metric.

FIG. 15 is a trace showing the pulsatile blood flow indicative of heartrate that is derived from the OCT data. In particular, the perfusionsignal of a well-perfused tissue site is aggregated and followed as afunction of time. Since the blood flow rate changes through a cycle of aheart beat, the perfusion signal provides a corresponding change, whichis shown in FIG. 14. Accordingly, the heart rate of a subject can befollowed.

It is understood that a number of variations on the methods describedherein are possible, including variations within the knowledge of oneskilled in the art. Indeed, numerous other steps can be added, orparticular step omitted (e.g., omitting the aligning step; or simplyperforming the site selection step on existing OCT data). Suchvariations are within the scope of the present invention.

ADDITIONAL EMBODIMENTS

While the present invention has been described in terms of specificmethods, structures, and devices it is understood that variations andmodifications will occur to those skilled in the art upon considerationof the present invention. For example, the methods and compositionsdiscussed herein can be utilized beyond the preparation of metallicsurfaces for implants in some embodiments. As well, the featuresillustrated or described in connection with one embodiment can becombined with the features of other embodiments. Such modifications andvariations are intended to be included within the scope of the presentinvention. Those skilled in the art will appreciate, or be able toascertain using no more than routine experimentation, further featuresand advantages of the invention based on the above-describedembodiments. Accordingly, the invention is not to be limited by what hasbeen explicitly shown and described.

All publications and references are herein expressly incorporated byreference in their entirety. The terms “a” and “an” can be usedinterchangeably, and are equivalent to the phrase “one or more” asutilized in the present application. The terms “comprising,” “having,”“including,” and “containing” are to be construed as open-ended terms(i.e., meaning “including, but not limited to,”) unless otherwise noted.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the invention.

1. (canceled)
 2. A method comprising: receiving, from an opticalcoherence tomography apparatus, an intensity data measurement for aregion of tissue; passing the intensity data measurement through a firstfrequency band filter having a first bandwidth to produce a firstoutput; passing the intensity data measurement through a secondfrequency band filter having a second bandwidth that is wider than thefirst bandwidth to produce a second output; and determining anindication of fluid flow in the region of tissue by comparing the firstoutput and the second output.
 3. The method of claim 2, wherein both thefirst bandwidth and the second bandwidth are centered at a same basefrequency.
 4. The method of claim 2 further comprising: in response todetermining a positive indication of fluid flow in the region of tissue,determining a blood analyte measurement based on at least some theintensity data measurement.
 5. The method of claim 4, wherein the bloodanalyte measurement comprises a measurement of at least one of: bloodglucose, blood hemoglobin, or blood oxygen.
 6. The method of claim 2,wherein determining the indication of fluid flow in the region of tissuecomprises: analyzing fringe frequency data in the first output and thesecond output.
 7. The method of claim 6, wherein analyzing fringefrequency data comprises: analyzing frequency modulation in the fringefrequency data in the first output and the second output.
 8. The methodof claim 6, wherein analyzing fringe frequency data comprises: analyzingamplitude modulation in the fringe frequency data in the first outputand the second output.
 9. The method of claim 8, wherein analyzingfringe frequency data further comprises: comparing speckle intensity inthe first output and the second output.
 10. The method of claim 2,wherein determining the indication of fluid flow in the region of tissuecomprises: comparing speckle intensity in the first output and thesecond output.
 11. The method of claim 2, wherein the intensity datameasurement comprises a backscattered wide band signal.
 12. A methodcomprising: receiving, from an optical coherence tomography apparatus,intensity data measurement for a region of tissue; passing the intensitydata measurement through a first filter to produce a first output;passing the intensity data measurement through a second filter toproduce a second output; analyzing fringe frequency data the firstoutput and the second output to determine an indication of fluid flow inthe region of tissue; and in response to determining a positiveindication of fluid flow in the region of tissue, analyzing theintensity data measurement to determine a blood analyte measurement. 13.The method of claim 12 further comprising: analyzing a plurality ofintensity data measurements for a same region of tissue to determine ablood analyte measurement.
 14. The method of claim 13, wherein theplurality of intensity data measurements are obtained at a plurality ofdepths in the same region of tissue.
 15. The method of claim 13, whereinthe plurality of intensity data measurements are obtained at a pluralityof times for the same region of tissue.
 16. The method of claim 12,wherein the blood analyte measurement comprises a measurement of atleast one of: blood glucose, blood hemoglobin, or blood oxygen.
 17. Themethod of claim 12, wherein determining the indication of fluid flow inthe region of tissue comprises: analyzing fringe frequency data in thefirst output and the second output.
 18. The method of claim 17, whereinanalyzing fringe frequency data comprises: analyzing frequencymodulation in the fringe frequency data in the first output and thesecond output.
 19. The method of claim 17, wherein analyzing fringefrequency data comprises: analyzing amplitude modulation in the fringefrequency data in the first output and the second output.
 20. The methodof claim 19, wherein analyzing fringe frequency data further comprises:comparing speckle intensity in the first output and the second output.21. The method of claim 20, wherein determining the indication of fluidflow in the region of tissue comprises: comparing speckle intensity inthe first output and the second output.